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Toxicology Mechanism

Mechanisms of Toxicology

Receptor Ligand Stereospecific. TCDD (Dioxin), PCBs, Estrogen
Dioxin (TCDD) Characteristics Heating organic compounds in the presence of chlorine (chemical synthesis procedures). Planar, stable (in body and environment), lipid soluble (slow elimination, not kidneys). Example : agent orange.
Dioxin Toxicity Animals : teratogen, male reproductive system, cancer (liver), wasting, change gene expression of P450s, Humans : chlorane (skin lesions, Russian politician), Sensitivities (Guinea Pig >>> Hamster, humans unknown).
Dioxin Mechanism Mechanism: Bind Ah receptor in cytosol (AhR-D) -> Nucleus (ARNT) -> change gene expression (DRES) -> proteins like p450's and others -> cause (unsure which) toxicity
PCBs Less toxic than dioxin. Chlorine can vary attachment site. Some are dioxin like with less affinity. Meta and para : higher affinity, change gene transcription. Ortho : non-planar, no affinity, different kind of toxicity.
Estrogen Estrogen like effects : Chrlorine compounds (like PCB's), furane coumadin (soy), diethylstilbetrol, Tamoxifen, RU489 (Antagonist)
Interference with Excitable Membranes Tetrodotoxin (Na channels), Organic Solvents (membrane fluidity), DDT (Na channel closing), Organophosphates (acetylcholinesterase). (All inhibit)
Volatile Organic Solvents Hydrocarbons and alcohols. CNS : disorientation, euphoria, unconscious, paralysis, convulsions, death because of respiratory and heart paralysis. Mechanism unknown. Cross lipid membranes. HASH DUDs get euphoria.
Specific Volatile Organic Solvents and Specific Effects Lower doses than CNS. Benzene : hematopoesis (metabolized), CCl4 : hepatotoxic (metabolized), methanol : renal + metabolic acids (formic acid), N-hexane : peripheral neuropathy, ethylene glycol ethers : reproductive system, dixoane (not dioxin) : cancer
Ethanol CNS : a : depres, c: WK, Liver: steat, hepa, coll scar, cirr, portal HT, GI : gastritis, peptic ulcers, Panc, Heart : vasodili, acute hypotherm, myop, arrhyth, Endocr, Cancer : GI, liver, FAS, Immune WIPED (WK, Immune, portal HT, Endocrine, Dilitation)
Inhibit Energy Production (ATP) Change membrane integrity, Ion Pump, protein synthesis, heart and brain most effected. Examples : CO2 : compete for Hb, NO2- : Hb oxidation, CN, H2S, Azide : Mito electron transport, Nitrophenol : uncouple oxidative phosphorylation, Fluroacetate : Krebs
NO2- Sources : Drugs, Food preperation : looks like table salt, well water : bacteria in spawn stomachs have increased pH get NO3- to NO2-.
NO2- Side Effects Cyanosis : chocolate brown blood, decreased BP, CV collapse, Abdominal pain, GI irritation : nausea, vomiting, headache, vertigo, change respiration and pulse, inc IOP, inc ICP (intracranial P), coma (70% metHb), cancer from meat CAR CIVIC(nitrosamine)
NO2- Mechanism and Treatment +2 Hb -> +3 Methb -> binds NO2-. 40% toxic, 70-80% death : hypoxia and vasodilitation (NO). Treatment : maintain ciruclation and respiration, transfusions, methylene blud (antidote), Ascorbic acids : works in long term only, not acute.
Methylene Blue Mechanisms +3 MetHb + NADH -> +2. Excess +3 MetHb needs methylene blue as catalyst via MB reductase (Diaphorase II) from NADPH
CN- Industry, fumigant, criminal, fires, nitroprusside metabolism. Rare but BAD. Heart and brain. Headache, anxiety (early), nausea, vomiting, arrhythmias, other CV, pulmonary edema, coma, seizures, shock, no cyanosis till resp failure, death. ACCESS
CN- Treatment Support heart, anticonvulsants, NaHCO3 for acidosis, 100% oxygen. antidotes : NO2- (+2 to +3) to push CN off, Thiosulfate donates sulfur to increase metabolism of CN- with Rhodanese.
Binding of Biomolecules Binding proteins : change enzyme or membrane transport. Examples : CN-, CO2 : Hb, Heavy Metals : -SH group. Decrease intracellular thiols : GSH : protective, examples : acetaminophen depletes GSH
Acetaminophen "Therapeutic misadventure". Liver (#1 drug induced liver damage). Metabolism: Good route: PAPS Sulfonotransformation + UDP-GA Gluconation -> 95% conjugated. Bad route: p450 -> NAPQ1 -> Bind macromolecules (hepatocytes)
Acetaminophen vs Aflatoxin Acetaminophen : Hepatotoxicity via parenchymal damage (acute), central lobar lesions (around central vein). Aflatoxin : Hepatotoxicity via parenchymal and bile duct epithelial cells, peripheral lesions
Aflatoxin Characteristics Mycotoxin from mold on grains and nuts (aspergillow), low dose, long exposure, acute liver damage and cancer. p450s metabolize -> epoxide (active) -> bind DNA and proteins (macromolecules).
Aflatoxin Mechanism Mechanism: Good route : AFB1 -> p450s -> oxidation to non-toxic. Bad route : p450 -> epoxide (active) -> bind proteins : acute liver toxicity OR bind DNA : liver cancer. GSH also plays a role. Bioactivity causes binding which causes issues.
Aflatoxin Susceptibility Age. G: gender. B: metabolism (variations p450), immunologic reactions, reserve capacity, absorption, distribution, comorbid. E: inflammation (co-inflammatory drug, shift to left), exposure, nutrition, GSH : diurnal, decreased in fasting.
Nucelic Acids DNA = nucleophile. Electrophiles bind (free radicles) -> cell death OR somatic mutation -> cancer
Benzopyrine Polycyclic aromatic hydrocarbon. p450 activates. Burning carbon containing fuels (charcoal, tar), bay binds DNA.
Benzopyrine Metabolism p450 -> epoxide (active) -> epoxide hydrase -> dihydrobiol (no DNA binding, still lipophyilic) -> p450s -> epoxide (epoxide hydrase can't catalyze) -> bind DNA -> cancer OR epoxide hydrase conjugationto inactive (minor route).
Benzopyrine Mechanism BP + G-C -> BP-G thinks A -> A-T, mutation : permanent and heritable, start carcinogenesis -> NEED INITIATOR THEN PROMOTER
Food Additives Delany says no to anyhthing that causes cancer but everyone eats so even 1/10,000 SEs is bad, because a million billion people times 1/10,000 = ALOT with cancer.
Drug Administration DES (anti miscarriage 50s) -> teen daughters in 70s with vaginal cancer (long latent period). Smoking increases lung cancer. To test, look at animals : bioassay, long latency, massive doses (spontaneous tumors do happen) extrapolate back a "safe dose".
Xenobiotic Metabolized and eliminated OR becomes reactive intermediate which can covalently bind and cause 1. peroxidation of lipid membrane (injury and necrosis), 2. Immune response (Hapten -> Ag), or 3. Bind macromolecules DNA and proteins (cancer).
Examble of Xenobiotic CCl4 -> CCL3-, O2-, OH-, etc... Membrane FAs with unsaturated side chains. LF -> opens to H-C* + H*. CCl4 -> p450 -> CCl3 (~stable) + LH -> CHCl3 + H* + L* -> L* + O2 -> LOO* (peroxil)+ LH -> LOOH (Peroxide lipid toxic with break down) + L* (cycle).
ROS 1 e- reduction of O2 -> O2-* (Superoxide) -> H2O2 both + Fe+2 -> OH* (hydroxyl) -> H20 (each time lose 1 e-) * = ROS, reactive and toxic. Paraqual forms ROS in cycle with NADPH + p450 -> NADP+ and O2 -> O2- : redox cycling.
Results of ROS Lipid peroxidation, GSH ox -> Disulfide, protein oxidation -> disulfide, depletion of NADH (reducin equivalents) -> lung problems.
Protection against ROS O2 -> O2-* + SOD -> H2O2 Both + Fe+2 -> OH* -> H20. H202 + GSH -> GSPx -> H20 + GSSH. GSSH + NADPH -> GSRed -> NADP+. SOD dec O2-*, GSPx dec H202 (less reactive than O2-*, GSRed inc GSH, Vit C + * -> H20, Vit E -> lipid + Vit C -> H20 soluble.
No protection 1. Vit E or Vit C deficiency, 2. Selenium deficiency (GSPx), 3. GSH depletion (malnutrition, fasting), 4. Genetic (SOD deficient). ALSO in ETC e- coupled tightly, from O2 right to H2O.
Oxidant NO2 <-> N2O2 (gas). Silos : bacteria incomplete breakdown of NO3-. Smog : nitrogen oxides + O2 + sun -> NO2 + O3 (ozone, toxic). SEs: bronchiolitis obliterans (silo fillers disease, can be 100,000 ppm) : small airway of lungs (100 ppm bad, 200 kills).
Oxidant Mechanism Direct + H20 (mucous) -> HNO3. Oxidation -> lipid peroxidiation -> apoptosis. In lungs get clara cells for normal cilia.
Calcium Issues of Homeostasis Increase cytosolic Calcium -> issues with cytoskeleton -> increase proteases, phospholipases and endonucleases (chompy, chompy), also issues with mito.
Increased Gene Expression Like Dioxin
Selective Cell Death MPTP -> parkinson’s, Thalidomide -> teratogen -> arm buds.
Teratogens Doses non-toxic to mom. Thalidomide -> arm buds. Window : organogenesis (critical periods). FAS, Vit A (high doses), synthetic retinoids (Accutane), Cocaine, Methyl Hg. Seg I = A + B + C, Seg II = B, Seg III = B + C (A = sperm, B = org, C = to wean).
Created by: chavezc3



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